CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.

A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations / Gennari M; Stratakis CA; Hovarth A; Pirazzoli P; Cicognani A.. - In: CLINICAL ENDOCRINOLOGY. - ISSN 0300-0664. - STAMPA. - 69:(2008), pp. 751-755. [10.1111/j.1365-2265.2008.03286.x]

A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations.

GENNARI, MONIA;PIRAZZOLI, PIERO;CICOGNANI, ALESSANDRO
2008

Abstract

CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.
2008
A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations / Gennari M; Stratakis CA; Hovarth A; Pirazzoli P; Cicognani A.. - In: CLINICAL ENDOCRINOLOGY. - ISSN 0300-0664. - STAMPA. - 69:(2008), pp. 751-755. [10.1111/j.1365-2265.2008.03286.x]
Gennari M; Stratakis CA; Hovarth A; Pirazzoli P; Cicognani A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/66838
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